Two is Company, but is Three Really a Crowd? Once Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD

Background: With the recent advancements in inhaler delivery systems there has been new developments for multi-drug options in a single inhaler. This is particularly useful for patients with advanced and symptomatic chronic obstructive pulmonary disease (COPD) who may require up to three classes of inhalation therapy: inhaled corticosteroids (ICS), long-acting B2-agonists (LABA), and long-acting muscarinic antagonists (LAMA). Daily administration of these maintenance medications is vital to avoid COPD exacerbations and hospitalizations. Using multiple inhalers with varying administration mechanisms can be overwhelming and confusing to patients. Thus, the introduction of one inhaler containing all three COPD therapies brings a novel product to the market that has the potential to improve patient adherence and outcomes.

Objective: Is single inhaler triple therapy as effective as the current therapy? A recently published study in The New England Journal of Medicine sought to answer this question.

Study Design: The Informing the Pathway of COPD Treatment (IMPACT) trial was a phase 3 study that analyzed the efficacy and safety of a triple therapy in one inhalation method as compared to dual therapy in a single inhaler. This randomized, double-blind, parallel-group study enrolled 10,355 participants age 40 years of age or older and had symptomatic COPD (COPD Assessment Test [CAT] score, ≥10. These patients had either a forced expiratory volume in one second (FEV1) that was less than 50% of the predicted normal value and a history of at least one moderate or severe exacerbation in the previous year, or an FEV1 of 50 to 80% of the predicted normal value and at least two moderate exacerbations or one severe exacerbation in the previous year. Participants were randomized into one of the three following groups: (1) once daily use of combination fluticasone 100 mcg + umeclidinium 62.5 mcg + vilanterol 25 mcg (triple therapy) (2) fluticasone 100 mcg + vilanterol 25 mcg (dual therapy) (3) umeclidinium 62.5 mcg + vilanterol 25 mcg (dual therapy), which were each administered in a single Ellipta inhaler. These treatments are consistent with recommendations from Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines. However, because patients were randomized, their assigned treatment study may not match corresponding recommended GOLD 2017 treatment according to FEV1 and patient symptoms. The patients were followed for 52 weeks, and the primary outcome the authors assessed was the annual rate of moderate or severe COPD exacerbations during treatment.

Results: The results of the study found that patients taking the triple therapy had an overall lower rate with 0.91 per year of moderate and severe exacerbations during treatment as compared with 1.07 per year with fluticasone-vilanterol dual therapy [95% CI 0.80-0.90; rate ratio with triple therapy, 0.85], and 1.21 per year with umeclidinium-vilanterol [95% CI 0.70-0.81; rate ratio with triple therapy, 0.75] (P<0.001). Safety analysis of the three trial groups showed similar effects, and no new findings were associated with the triple therapy inhaler. Some of the side effects noted by the investigators included anticholinergic side effects, cardiovascular effects (hypertension, arrhythmias), and rates of pneumonia infections. Lung function was measured by mean change in trough forced expiratory volume (FEV1) from baseline. Triple therapy showed improved lung function as compared to both groups [difference of 97 mL between triple therapy and fluticasone-vilanterol group (95% CI, 85-109, P<0.001), and 54 mL difference between triple therapy and umeclidinium-vilanterol groups (95% CI, 39-69, P<0.001)]. The investigators found there were no clinically relevant differences in lab values including ECG, vital signs, or other clinical laboratory values.

Conclusion: The authors concluded that once-daily single-inhaler triple therapy with fluticasone, umeclidinium, and vilanterol resulted in significantly lower rates of moderate or severe COPD exacerbations. The results of this head-to-head trial look promising.

Key Point: For patients who may require triple therapy, an option that offers all three in one inhaler would be ideal for improved adherence. Future research may demonstrate long-term impacts of this novel therapeutic combination.